Pharmacovigilance involves the collection, detection, assessment, monitoring, and prevention of adverse events with pharmaceuticals. The Mayo Clinic reports that up to 70 percent of Americans take prescription drugs, more than half take two prescription drugs, and up to 20 percent of patients take five or more. Polypharmacy plays a central therapeutic role in the treatment of complex, multifactorial disorders but also exposes patients to elevated risks of drug-drug interactions (“DDIs”). Nearly a million injuries or deaths are attributed to adverse events, 30% of which are DDI-related. Novel drug-associated adverse effects may be evident post-approval, leading to patient safety concerns and possibly withdrawal of drugs by the U.S. Food and Drug Administration (“FDA”). For instance, troglitazone with withdrawn in 2000 due to increased risk of hepatotoxicity, while cerivastatin was withdrawn in 2001 due to increased risk of rhabdomyolysis. These effects may be missed during clinical trials, which stress the importance of post-approval pharmacovigilance. Concomitant drugs may also be inadvertently introduced to patient-drug regimen in response to multiple clinical indications, thereby exacerbating the risk of DDI-associated adverse events. This may occur more often when a patient sees multiple clinicians. Pharmacologic adverse events, therefore, provide a strong incentive for reporting clinical indications, drug exposures, and both short and long-term clinical outcomes.
The FDA and the World Health Organization (“WHO”) are two exemplary institutions worldwide that pursue pharmacovigilance and monitor safety standards of approved drugs on the market. The FDA maintains the Adverse Events Reporting System (“FAERS”), which stores manually-reviewed adverse event reports received by the FDA from healthcare professionals, manufacturers, and consumers from the United States and around the world. Each patient report contains one or more demographic details such as age and gender, clinical indications, drugs, adverse events, and outcomes. These reports are made available with the principal goal of identifying of latent risks of approved therapeutics and their combinations. The spontaneous nature of FAERS suggests a likelihood of data redundancies and duplications; however, with a combination of prudent data-cleaning mechanisms, duplication removal, and adoption of variety of data-driven approaches, the FAERS data has shown significant phenome-pharmacome associations capable of generating testable hypotheses.
Existing FAERS-mining web-data resources such as the Drugcite service, the AdverseEvents service, the FDAble service, and the OpenVigil service use standard pharmacovigilance approaches to highlight drug-adverse event associations and are limited to basic queries. Several services make use of a proportional reporting ratio, which is a measure of the frequency with which a particular adverse event is reported for a drug of interest versus the frequency with which the same adverse event is reported for drugs in a comparison group (which may comprise a second particular drug, a class of drugs, etc.). The AERS Spider service provides interactive exploration of drug-adverse event relationships by removing disproportionately distributed mask factors, since the use of a proportional reporting ratio without accounting for these mask factors may lead to inaccurate inferences about drug-adverse event relationships. However, these resources do not provide the capability of ontological aggregations and high-dimensional cohort-based analyses to identify potential risk-augmenting drug interactions in population subgroups. In comparison, AERSMine aggregates FAERS data into mineable matrices from mutually exclusive sets and allows for exploratory and investigative analyses to generate testable hypotheses. Further, AERSMine, unlike other available resources, allows one to conduct large-scale, population subgroup-specific studies across multiple treatments and indication cohorts, to recognize inter-correlations, and to make cross-comparisons for better understandings of therapeutic toxicities associated with pharmacological agents. AERSMine-facilitated hypotheses and safety signals can be further reviewed by consortia such as SONAR, and enable additional AE-specific investigations. Reporting back such findings to the FDA can initiate the process of more closer and systematic scrutiny of drug-related novel AEs, ultimately warranting changes in the drug labels. For instance, safety concerns identified and reported to the FDA by SONAR (such as (a) Reye's syndrome for acetylsalicylic acid; (b) pure red cell aplasia for erythropoietin; and (c) nephrogenic systemic fibrosis for gadodiamide) are accurately detected via AERSMine. The complementary nature of AERSMine and SONAR, and the importance of SONAR clinical review, will be valuable for pharmacovigilance.